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Structure of 1-Methyl-4-piperidone
CAS No.: 1445-73-4
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 1445-73-4 |
Formula : | C6H11NO |
M.W : | 113.16 |
SMILES Code : | CN1CCC(=O)CC1 |
MDL No. : | MFCD00006191 |
InChI Key : | HUUPVABNAQUEJW-UHFFFAOYSA-N |
Pubchem ID : | 74049 |
GHS Pictogram: |
![]() |
Signal Word: | Danger |
Hazard Statements: | H225 |
Precautionary Statements: | P210-P233-P240-P241-P242-P243-P280-P303+P361+P353-P370+P378-P403+P235-P501 |
Class: | 3 |
UN#: | 1224 |
Packing Group: | Ⅲ |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.83 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 35.85 |
TPSA ? Topological Polar Surface Area: Calculated from |
20.31 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.54 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.28 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.1 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.07 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.1 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.47 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.37 |
Solubility | 48.8 mg/ml ; 0.431 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
0.31 |
Solubility | 233.0 mg/ml ; 2.06 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.82 |
Solubility | 17.0 mg/ml ; 0.151 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.19 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.0 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With ammonia; In methanol; at 50℃;Schlenk technique; | In a schlenk reactor, a solution of <strong>[14150-94-8]1-methyl-3,5-dinitro-1H-pyridin-2-one</strong> (5.00 g, 25.11mmol) and 1-methyl-4-piperidone (3.13 g, 27.62 mmol) in ammonia (7N in MeOH) (43mL) was stirred overnight at 50 C. After cooling down to rt, the mixture was evaporatedin vacuo, taken-up in DCM and a saturated aqueous solution of NaHCO3 was added. Thelayers were separated and the aqueous layer was extracted with DCM (three times). The combined organic layers were dried over MgSO4, filtered off and evaporated in vacuo togive 2.32 g of intermediate 128 (48% yield, reddish solid) which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In ethanol; water; at 60℃; for 16.0h; | Reference Example 65 2-methyl-1,2,3,4-tetrahydrobenzo[b][1,6] naphthyridin-7-amine A solution of <strong>[98276-57-4]2,4-diaminobenzaldehyde</strong> (1.00 g, 7.34 mmol), 1-methyl-4-piperidinone (1.08 ml, 8.81 mmol) and 4N aqueous sodium hydroxide solution (11 ml) in ethanol (70 ml) was stirred at 60C for 16 hrs, and the solvent was evaporated under reduced pressure.. The residue was dissolved in ethyl acetate, washed with aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate.. The obtained crude product was purified by NH-silica gel chromatography (elute solvent; ethyl acetate) and treated with ethyl acetate - isopropyl ether (1:5) to give the title compound (666 mg) as a powder.1H-NMR (DMSO-d6) delta: 2.37 (3H, s), 2.71 (2H, t, J = 6.0 Hz), 2.96 (2H, t, J = 6.0 Hz), 3.56 (2H, s), 5.58 (2H, br), 6.80 (1H, d, J = 2.1 Hz), 6.87 (1H, dd, J = 2.1, 8.4 Hz), 7.48 (1H, d, J = 8.4 Hz), 7.64 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In ethanol; | EXAMPLE 4 1'-Methyl-5,6-dihydrospiro[1H-indolo[3,2-c]quinoline-6,4'-piperdine] To a solution prepared from 8 g of <strong>[32566-01-1]2-(2-aminophenyl)indole</strong>, 2.5 ml of acetic acid and 100 ml of ethanol was added 5.15 g of 1-methyl-4-piperidone. The mixture was refluxed for 6 hours. Concentration gave a gum which was triturated with dilute NH4 OH and the resultant solid was collected. Flash chromatography using 10% CH3 OH/CH2 Cl2 as an eluent gave 4.15 g of yellow solid, m.p. 228-230 dec. Analysis. Calculated for C20 H21 N3: 79.17% C, 6.98% H, 13.85% N. Found: 78.85% C, 7.09% H, 13.68% N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; | EXAMPLE 12 A solution of 11.3 g. of 1-methylpiperidin-4-one in 120 ml. of ether is added dropwise to a stirred isoquinolyl-1-lithium solution, freshly prepared from 20.8 g. of <strong>[1532-71-4]1-<strong>[1532-71-4]bromoisoquinoline</strong></strong> and n-butyllithium in 400 ml. of ether, at 0°, under dry nitrogen. The mixture is stirred for 2 hours more at 0°. Water (50 ml.) and then 100 ml. of 5percent hydrochloric acid are added dropwise to decompose the lithium 1-methyl-4-(1-isoquinolyl)-piperidin-4-olate formed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a suspension of <strong>[62830-55-1]4-iodophenylhydrazine hydrochloride</strong> (2.0 g, 0.0074 mol) in dioxane (30 mL) at RT was added cone. H2SO4 (0.7 mL, 0.0171 mol) dropwise and the reaction mixture was stirred for 5 min. To this was added N-methyl-4-piperidone (0.838 g, 0.0074 mol) and the reaction mixture was stirred at RT for 10 min and heated at 70 0C for 90 min. Reaction monitored by TLC. The solvent was evaporated and pH adjusted to 9-10 by 10percent KOH Solution. The product was extracted with (3x50 rnL) EtOAc. Combined organic layer washed with water and brine and dried over sodium sulfate, concentrated under vacuum and product purified by column chromatography (100-200 mesh silica) in solvent system (0-10percent, DCM/MeOH). Obtained 1.8g of brown solid. 1U NMR (CDCl3, free base) d (ppm) 7.70 (s, IH), 7.38 (d, IH), 7.05 (d, IH), 3.60 (s, 2H), 2.90 (m, 4H), 2.58 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With sodium methylate; In methanol; at 20℃; for 4h; | General procedure: Method A [31]: To a solution of the starting aldehyde (1.5 mmol) and ketone (0.75 mmol) in methanol (10 mL) was added the solution of sodium methoxide in methanol (5.4 M, 0.14 mL,0.75 mmol), and the mixture was stirred for 4-18 h and monitored with TLC. When the reaction was completed, the following two work-up procedures were applied. Procedure 1: if precipitate was observed, the precipitate was filtered and rinsed with cold methanol. Procedure 2: if no precipitate was observed, then saturated solution of ammonium chloride was added, and the subsequent mixture was extracted with dichloromethane. The organic layer was dried over anhydrous MgSO4. The solvent was evaporated under vacuum to give a crude product, which was purified by preparative TLC (3e5% methanol in dichloromethane) or column chromatography (2% methanol in dichloromethane). |
49% | With sodium methylate; In methanol; | [0067] The solution of sodium methoxide in methanol (5.4M, 0.14 mL, 0.75 mmol) was added to a solution of 5-methylisoxazole-3-carbaldehyde (166.5 mg, 1.5 mmol) andN-methylpiperidone (85 mg, 0.75 mmol) in methanol (10mL). The mixture was stirred for 4 h -18 h and monitored withThin Layer Chromatography (TLC). When the reaction wascompleted, saturated solution of ammonium chloride wasadded, and the subsequent mixture was extracted with dichloromethane.The organic layer was dried over anhydrousMgS04 . The solvent was evaporated under vacuum to give acrude product, which was purified by preparative TLC (5%methanol in dichloromethane ).[0068] NMR spectra were obtained on a Bruker Fourier300spectrometer in CDC3, CD30D, or DMSO-d6. The chemicalshifts are given in d (ppm) referenced to the respective solventpeak, and coupling constants are reported in Hz. All reagentsand solvents were purchased from commercial sources andwere used without further purification. Silica gel columnchromatography was performed using silica gel (32-63 pt).Preparative thin-layer chromatography (PTLC) separationswere carried out on 1000f1AnaTech thin layer chromatographyplates (Lot No. 13401).[0069] (2E,6E)-2,6-Bis((5-methylisoxazol-3-yl)methylene)cyclohexanone (general formula (I), 5BHR-124 sidegroup, shown as Compound 8 in Table 4) was prepared in49% yield as a yellow crystal: mp. 155-156 C. IR (neat) v max:3129, 2943, 1685, 1636, 1598, 1426, 1267, 1181, 910, 783cm-1.1H NMR (300 MHz, CD3Cl) o. 2.47 (s, 6H), 2.52 (s,3H), 3.90 (s, 4H), 6.11 (s, 2H), 7.42 (s, 2H). 13C NMR (75MHz, CD3Cl) o. 12.2, 45.7, 57.5, 103.6, 121.9, 138.1, 158.8,169.9, 186.5. HR-MS (ESI) m/z: calcd for C16H18N30 3[M+H]: 300.1348. found 300.1345. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With sodium hydroxide; In ethanol; at 5 - 27℃; | General procedure: The a,b-unsaturated carbonyl-based cyclohexanone compoundswere synthesized using direct coupling method as reportedpreviously28,37 (Table 2). The ketones were reacted with suitablearomatic aldehyde at molar ratio 1:2 using base-catalyzed claisen-schmidt condensation to synthesize 21 new compounds (3a?3u). Characterization data of only three compounds (3c, 3f, 3o)was reported previously.37 The flow diagram for the synthesis ofa,b-unsaturated carbonyl-based compounds is shown in Scheme 1.The ketone (10 mmol, 1 equiv) and aromatic aldehyde (20 mmol,2 equiv) were mixed in round bottom flask using 25 mL ethanolat 5 C. 40percent sodium hydroxide solution (in ethanol) was added tothis solution. The mixture was stirred for 1?24 h at 27 C. The precipitateappearance and color variation indicated product formation.The reaction was monitored using TLC while acidified icewas added to stop it when completed. Recrystallization and/or columnchromatography were used to isolate the compounds. 4.3.14 3,5-Bis-(2-chloro-3,4-dimethoxy-benzylidene)-1-methyl-piperidin-4-one (3n) Yield: 61percent; Mp: 144-145 °C; 1H NMR (500 MHz, CDCl3) delta: 7.87 (s, 2H), 6.92 (d, J = 8.5 Hz, 2H), 6.55 (d, J = 8.5 Hz, 2H), 3.82 (s, 12H), 2.78 (s, 4H), 2.14 (s, 3H); 13C NMR (500 MHz, CDCl3) delta: 185.5, 149.7, 147.4, 145.1, 142.2, 135.8, 132.1, 105.7, 98.7, 56.8, 56.5, 41.5, 17.1; HRMS (ESI) m/z: 479.55 [M+H]+, Microanalysis calculated for C24H25Cl2NO5 (478.37): C, 60.26; H, 5.27; N, 2.93. Found: C, 60.52; H, 5.45; N, 2.72. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With sodium hydroxide; In ethanol; at 5 - 27℃; | General procedure: New a, b-unsaturated carbonyl-based compounds (5a-g and 6au)were synthesized using direct coupling technique [40] (Scheme 1). The reaction was carried out using base-catalyzed Claisen-Schmidt condensation reaction, by reacting different types of ketoneswith appropriate aromatic aldehyde at molar ratio 2:1 tosynthesize new compounds (5a-g) and at molar ratio 1:1 for (6a-u).For synthesis of 6a-u first 5a-g intermediates were synthesized andin second step appropriate aldehydes were reacted with intermediates.The detailed method of synthesis has already beenreported by us previously [38,40]. Scheme 1 shows the highlights ofsynthesis of compound 3, 4 and a, b-unsaturated carbonyl-basedcompounds along with oxime derivatives. 15 mL ethanol wastaken in a round bottom flask and aromatic aldehyde (20 mmol, 2equivalent) and specific ketone (10 mmol,1 equivalent) were addedand dissolved using a stirrer for 2-3 min at 5 C. Into the abovesolution, 40% NaOH solution in ethanol was added drop wise andthe mixture was stirred for 1-24 h at 27 C. The color change andprecipitate formation in the reaction mixture showed productformation. TLC was used to monitor the reaction and acidified icewas added to quench the reaction once completed. The isolation ofcompounds was done by recrystallization and/or by using columnchromatography. |
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